Within this application several publications are referenced by Arabic numerals. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entirety are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
The transition of T and B lymphocytes from their resting state to a state of functional maturity involves distinct steps of activation, proliferation and differentiation, each requiring specific signals.
Activation is initiated after antigens, mitogens or antibodies interact with the T-cell antigen receptor complex or with B-cell-surface immunoglobulins.
Activated T lymphocytes produce the growth promoting lymphokine interleukin-2 (IL-2) and express high affinity receptors for IL-2. For clonal expansion, and thus for specific T-cell immune responses to take place, the IL-2 receptor must interact with IL-2.
Similarly, the proliferation and subsequent differentiation of B lymphocytes is also regulated by at least two distinct types of lymphokines: one which promotes their growth (B cell growth factor or BCGF) and the other their differentiation into immunoglobulin secreting cells (B cell differentiation factor or BCDF) [l-4]. These lymphokines are produced primarily by T lymphocytes although B cells activated with Staphylococcus aureus Cowan l (SAC) [5,6] or transformed with Epstein Barr Virus (EBV) are also capable of secreting autocrine growth factors [6,10]. Recently some of those factors have been characterized biochemically, and the gene coding the synthesis of at least one of them has been cloned [4]. However, the molecular structure of the B cell receptor(s) for growth and differentiation factors is still unknown.
The identification and characterization of such receptors is of obvious importance for understanding the mechanisms which regulate the growth and differentiation of B-lymphocytes.
Several studies have reported on monoclonal antibodies specific for resting [22,23] or for activated B lymphocytes [24] that inhibit [23,24] or, alternatively, promote [22] the activation and differentiation of B lympoocytes. Monoclonal antibodies reacting with molecules involved in leukocyte cell interaction were also shown to mimic the biological effects of B cell stimulatory factors suggesting that they react with molecules associated with BCGF-receptor structures [25].
However, none of these monoclonal antibodies blocked the receptor of activated B cells for BCGF or BCDF. Monoclonal antibody (MoAb) NDA.sub.3 fulfills this essential criterion on which the definition of a receptor depends, i.e. it inhibits the interaction of the receptor with its ligand.
The newly developed MoAb NDA.sub.3 provides a tool for studying the mechanism of BCGF-R expression and internalization and of transmission of the proliferation signal.